Clinical improvement may not reflect metabolic homeostasis normalization in subjects with and without Roux-En-Y bariatric surgery after 12 years: comparison of surgical subjects to a lean cohort

Background: A 12-year study comparing clinical outcomes following Roux-en-Y bariatric surgery showed long-term weight loss with remission/prevention of type-2-diabetes (T2D), hypertension and dyslipidemia. However, it is unknown whether the underlying homeostatic metabolic processes involving hepatokines, adipokines and myokines also normalize. Using this 12-year study, we determined whether metabolic indices improved in post-surgical (BMI:34.4kg/m2) versus non-surgical comparator-subjects-with-obesity (BMI:43.8kg/m2) at 12-year follow-up (both cohorts with baseline diabetes), and if post-surgical subjects normalized their metabolic processes to those of a normal-weight cohort without diabetes. Methods: Cross-sectional design. Plasma from a cohort of Roux-en-Y bariatric surgery (n=50) and non-surgery (n=76) comparator-subjects-with-obesity (both cohorts at 12-year follow-up) plus a normal-weight cohort (n=39) was assayed by Luminex immunoassay or ELISA for hepatokines [angiopoietin-like proteins-(ANGPTL3; ANGPTL4; ANGPTL6); fibroblast growth factors-(FGF19; FGF21; FGF23)]; adipokines [adipsin; adiponectin; FGF19] and myonectin. Results: After age and gender adjustment, surgery versus comparator-subjects-with-obesity had lower BMI (34.4 ± 1.0 vs 43.8 ± 0.9kg/m2; p Conclusion: Bariatric surgery markedly improved anthropometric and metabolic features versus comparator-subjects-with-obesity at 12-year follow-up, indicating benefit of weight loss. However, despite weight loss, these patients still had class-1 obesity, as reflected in the adipokine, hepatokine and myokine markers of body homeostasis that did not completely normalize to indicative values of normal-weight subjects, suggesting either that this is the new normal for these patients or that weight loss to a BMI<25kg/m2 is needed for normalization of these parameters.</p

Effects of a 2 hour 75 g OGTT on serum glucose (A), insulin (B) and cartonectin (C) concentrations in T2DM subjects (<i>n</i> = 47).

<p>Group comparison by Wilcoxon matched pairs test. **<i>P</i><0·01.</p

Linear regression analysis of variables associated with Cartonectin.

<p>Linear regression analysis of variables associated with Cartonectin.</p

Clinical, hormonal and metabolic features of study subjects.

<p>Clinical, hormonal and metabolic features of study subjects.</p

The role of FGF21 activated signalling pathways in cardioprotection.

<p>Fig. 3A1: Cardiomyocytes treated with FGF21 (100 nM) for 5–30 minutes. Phosphorylated ERK_1/2 [Fig. 3A1]; Akt [Fig. 3A2] and AMPK [Fig. 3A3] proteins are represented in relation to total proteins, expressed as fold increase over basal. ***P<0.001, **P<0.01, *P<0.05 vs. basal, n = 6 per group. Fig. 3B1: RPP with ischemia/reperfusion and FGF21 treatment following pre-incubation with inhibitors (TO-901317; wortmanin; Compound C or U0126) ^aP<0.05, ^bP<0.01 vs. FGF21 only treatment, n = 6 per group. Fig. 3B2: Infarcted area (%) following ischemia/reperfusion and FGF21 treatment following pre-incubation with inhibitors (TO-901317; wortmanin; Compound C or U0126) **P<0.01, *P<0.05 vs. FGF21 treated, n = 6 per group.</p

Experimental design.

<p>Following 30(t0), treatments were given for 10 mins followed by 10 minutes washout (normal tyrodes) and subsequently global ischemia was induced for 30 mins by cessation of tyrodes inflow, maintained at 37°C, followed by 120 mins reperfusion. Infarct size determination was performed subsequently.</p

Autocrine/paracrine effects of FGF21 in rat cardiomyocytes.

<p><b>Fig. 4A</b>:FGF21 mRNA expression levels in cardiomyocytes following FGF21 (100 nM) treatment with or without pathway inhibitors [(U0126; wort (wortmanin); Comp C (Compound C) or TO (TO-901317)] (normalised to GAPDH and expressed as fold changes over basal).<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087102#pone-0087102-g004" target="_blank"><b>Fig. 4B</b>:</a> Graphical analysis of FGF21 protein levels following FGF21 treatment. <b>Fig. 4C</b>: Graphical representation of FGF21 ELISA measurements in the conditioned media following FGF21 treatment. <b>Fig. 4D</b>: Graphical representation of FGF21 ELISA measurements of rat heart Langendorff exudates following global ischemia for 5–30 mins and 120 mins of reperfusion; with or without prior FGF21 (100 nM) infusion. Data shown are means ± SEM of triplicates. The values represented are relative to basal. ***<i>P</i><0.001; **<i>P</i><0.01; *<i>P</i><0.05 vs. FGF21 only treated, <b>^a</b><i>P</i><0.001 vs. basal, n = 6 per group.</p

Effect of moderate aerobic exercise on complement activation pathways in polycystic ovary syndrome women

Background: The complement system is pivotal in host defense mechanisms, protecting against pathogenic infection by regulating inflammation and cell immunity. Complement-related protein activation occurs through three distinct pathways: classical, alternative, and lectin-dependent pathways, which are regulated by cascades of multiple proteins. Complement activation is recognized in polycystic ovary syndrome (PCOS) to be associated with obesity and insulin sensitivity. Exercise reduces insulin resistance and may help reduce obesity, and therefore, this study was undertaken to determine the effect of exercise on the activation of complement-related proteins in PCOS and control women. Subjects and measurements: In this study, 10 controls and 11 PCOS subjects who were age- and weight-matched underwent an 8-week supervised exercise program at 60% maximal oxygen consumption. Weight was unchanged though insulin sensitivity was increased in PCOS subjects and controls. Fasting baseline and post-exercise samples were collected and 14 complement-related proteins belonging to classical, alternative, and lectin-dependent pathways were measured. Results: Baseline levels of complement C4b and complement C3b/iC3b were higher in PCOS (P P P P P P P Conclusion: Exercise induced complement changes in controls that were not seen in PCOS subjects, suggesting that these pathways remain dysregulated even in the presence of improved insulin sensitivity and not improved by moderate aerobic exercise. Clinical trial registration: ISRCTN registry, ISRCTN42448814.</p

Differences in Cardiac Function, Infarct Size and FGF21 autocrine secretory pattern in lean and obese hearts treated with FGF21.

<p>LVDP (mmHg) and left ventricular contractility (dp/dt) in obese control (saline treated) groups [<b>Fig. 7A1</b>], obese (FGF21 treated) groups [<b>Fig. 7A2</b>] and lean (FGF21 treated) groups [<b>Fig. 7A3</b>]; following global ischemia and reperfusion. Graphical representation of the infarcted area (%) in obese control, obese and lean FGF21 (100 nM) treated rat hearts following global ischemia and reperfusion [<b>Fig. 7B</b>]. Graphical representation of FGF21 levels in obese and lean FGF21 (100nM) pre-treated rat heart coronary effluents following global ischemia and reperfusion [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087102#pone-0087102-g006" target="_blank"><b>Fig 6C</b></a><b>]</b>. Data shown are means ± SEM of triplicates. The values represented are relative to basal. <b>^***</b><i>P</i> < 0.001 vs. t [0] time point, <b>^#</b><i>P</i> < 0.05 vs. lean at t(5); n  =  6 per group.</p

Identification of FGF21mRNA, protein and the effect of recombinant FGF21 on cardiac function and infarct size.

<p>FGF21 mRNA [<b>Fig. 2A1</b>] and protein expression [<b>Fig. 2A2</b>]; βKlotho mRNA [<b>Fig. 2A3</b>] and protein expression [<b>Fig. 2A4</b>] in isolated rat cardiomyocytes [A] and rat heart [B]. Fig<b>.</b> 1B:Immunocyto/histochemistry and confocal analysis of FGF21 protein in isolated adult rat cardiomyocytes [<b>B1</b>] and rat heart [<b>B2</b>]. MW.- Molecular Weight Marker for PCR products; BP.- Base Pairs; kDa.-kilo daltons. <b>Fig. 2C</b>-(<b>a</b>): Trace recordings of left ventricular developed pressure [LVDP (mmHg)] and left ventricular contractility (dp/dt) in control (saline treated) groups; and <b>Fig. 2C</b>-(<b>b</b>):[LVDP-mmHg] and dp/dt ratio in FGF21 treated groups - following 30 mins of global ischemia and 120 mins reperfusion. <b>Fig. 2D:</b> Rate pressure product [RPP (mmHg/min)] during global ischemia and reperfusion with or without FGF21 treatment [**<i>P</i><0.01 vs. control]. <b>Fig. 2E</b>: Graphical representation of infarct area (%) in rat hearts treated with or without FGF21. Data shown are means ± SEM (n = 6, in triplicates). ***P<0.001; **P<0.01 vs. control.</p